Clinical Trials Register

Summary
EudraCT Number:	2018-000752-18
Sponsor's Protocol Code Number:	17-924
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-02-19
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2018-000752-18

A.3

Full title of the trial

Ajmaline provocation in asymptomatic PLN and PKP2 mutation carriers for early detection of Arrhythmogenic Cardiomyopathy

Ajmaline provocatie in asymptomatische mutatie dragers van PLN and PKP2 mutaties ter vroeg herkenning van aritmogene cardiomyopathie.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Ajmaline infusion for early detection of arrhythmogenic cardiomyopathy

Vroeg herkenning van aritmogene cardiomyopathie doormiddel van medicatie toediening en uitgebreide hartfilmpjes.

A.3.2

Name or abbreviated title of the trial where available

Ajmaline provocation in ACM

Ajmaline provocatie in ACM

A.4.1

Sponsor's protocol code number

17-924

A.5.4

Other Identifiers

Name:

The Netherlands National Trial Register

Number:

NTR 7039

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	UMC Utrecht
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Hartstichting
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UMC Utrecht
B.5.2	Functional name of contact point	Dr. KP. Loh
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 100
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+310887551554
B.5.6	E-mail	p.loh@umcutrecht.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Gilurytmal
D.2.1.1.2	Name of the Marketing Authorisation holder	CARINOPHARM GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ajmaline
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Arrhythmogenic cardiomyopathie due to PLN or PKP2 mutations, asymptomatic family members who are carriers of PLN or PKp2 mutations, patients without structural heart disease who are referred for ajmaline provocation to exclude brugada syndrome

Aritmogene cardiomyopathie door mutaties in het PLN of PKP2 gen, asymptomatische familieleden met een pathogene mutatie in PLN of PKP2, patiënten met een verdenking op Brugada syndroom en een sturctureel normaal hart welke verwezen zijn voor een ajmaline provocatie test.

E.1.1.1

Medical condition in easily understood language

Patients with arrhythmogenic cardiomyopathy due to PLN or PKP2 mutations and their family members, patients who are referred to exclude Brugada syndroom by ajmaline test

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Describe the electrocardiographic changes and areas of late myocardial activation encountered in PLN and PKP2 mutation carriers, patients and controles during ajmaline provocation . And use this information for the detection of early stages of arrhythmogenic cardiomyopathy

E.2.2

Secondary objectives of the trial

Describe patterns of early arrhythmogenic cardiomyopathy on electrocardiographic imaging
Describe the effects of ajmaline on the myocardial activation times using electrocardiographic imaging and the electrocardiogram
Describe the effects of ajmaline provocation in this patients group
Describe the effects of ajmaline on the liver test parameters 2 weeks after administration

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age ≥18 years
Pathogenic PLN mutation, pathogenic PKP2 mutation or patients without structural heart disease who are referred for ajmaline provocation to exclude Brugada syndrome.
Referral for cardiac MRI during routine clinical practice
New York Heart Association functional class ≤ 1.

E.4

Principal exclusion criteria

Severe hepatic impairment (Child-Pugh class C)
Severe renal dysfunction (eGFR <30 ml/min/kg)
Symptomatic heart failure, NYHA ≥ 2
Women who are currently pregnant
Known intolerance or contraindication to Ajmaline
Sick sinus syndrome, second or third degree AV block
Recent myocardial infarction
Known strong allergic reaction to ECG electrodes

E.5 End points

E.5.1

Primary end point(s)

The mean difference in local Activation Time Duration before ajmaline administration and at the maximal amount of ajmaline administration in the subtricuspid area, the mid right ventricle area, right ventricular outflow tract, the left ventricle anterior area and left ventricle posterolateral area as calculated by ECG imaging.

E.5.1.1

Timepoint(s) of evaluation of this end point

Before, during an at ajmaline dose maximum during ajmaline provocation.

E.5.2

Secondary end point(s)

Mean differences in epicardial and endocardial Activation Time Duration before and at the maximal amount of ajmaline administration in these specified areas (subtricuspid area, the mid RV area, RVOT, the LV anterior and LV posterolateral) as calculated by ECG imaging.
Electrocardiographic parameters (PQ, QRS and QTc intervals, the occurrence of the type I Brugada pattern, terminal activation duration) before, during and directly after ajmaline provocation.

Other study parameters:
Patient demographics: Sex, Age, Past medical history (including previous episodes of ventricular tachycardia and the results of cardiovascular diagnostic test, for example cardiac holters, cardiac MRI and echocardiography), Allergies, Family history of sudden cardiac death, the amount of 2010 Task Force Criteria points for arrhythmogenic cardiomyopathy (ACM) currently used medication, Weight (kg), Length (cm), Body mass index.

Laboratory parameters: Before ajmaline provocation: Creatinine and GFR, Sodium, Potassium, ALAT, ASAT, GGT, AF, bilirubin.
Two weeks after ajmaline provocation: ALAT, ASAT, GGT, AF, bilirubin.

E.5.2.1

Timepoint(s) of evaluation of this end point

Directly during ajmaline provocation for electrocardiographic parameters and adverse events
At 2 weeks after ajmaline provocation to test liver parameters

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Diagnostic agent used in the cohorts

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS, after that patients will stay part follow up in the national arrhythmogenic cardiomyopathy registry.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2019-02-19.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Treatment is not part of the study and is up to decision of the treating physician of the patients.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-02-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-24

P. End of Trial
P.	End of Trial Status	Ongoing

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